PROJECT SUMMARY/ABSTRACT There has recently been a dramatic increase in incidences of neurodevelopment disorders (NDDs) in children. For instance, autism spectrum disorders have increased from 1 in 2000 people in 1980s to the recently reported 1 in 68 as reported by the CDC. In addition, instances of primary microcephaly due to Zika virus exposure have gained global attention, and birth defects caused by thalidomide and prenatal alcohol exposures highlight the importance of developing suitable model systems to understand, detect, and treat causes of these disorders. The importance of vascular tissue development and its contributions to disease pathologies are often overlooked, as the focus is instead on the role of neural and glial cell types. However, a number of neurodevelopmental and neurodegenerative disorders are directly associated with vascular malformations, including microcephaly, cerebral cavernous malformations, autism, Alzheimer?s disease, Alexander?s disease, and Rett syndrome. The developing brain is at its most vulnerable during the early stages of neurodevelopment, and one key point of vulnerability is the initial vascularization of the developing brain from the associated perineural vascular plexus (PNVP), where the blood brain barrier has yet to fully form. There is to date no human model that mimics the brain vasculature at this critical stage. We propose to generate a neurovascular microphysiological system (NV- MPS) that mimics the initial vascularization of the developing brain and to progress the model to support the long term maintenance of an engineered reproducible brain organoid. The proposed studies will achieve three specific aims. Specific Aim 1 will create a developing brain microphysiological system (MPS) using a tubeless microfluidics device, synthetic hydrogels and human PSC-derived cell types. Specific Aim 2 will generate models of a diseased developing brain and measure molecular, cellular and tissue level outputs that have been identified to be indicators of perineural vascular plexus formation, neurovascular integration and subsequent cortical maturation. Specific Aim 3 will measure and stimulate neuronal electrophysiological function in the NV-MPSs using integrated cellular reporters and optically transparent embedded electrodes. Completion of this research will provide a simple, robust and reliable NV-MPS that will provide the means to study the initial vascularization of the developing brain, the neurovascular contributions to neurological disorders and a means to test the effect of xenobiotic exposures at the early stages of neural development and finally will create a perfusable vasculature that feeds and maintains engineered neural organoids.